Lesperienza di Verona Massimiliano Bonifacio only considering Acute - PowerPoint PPT Presentation

L’esperienza di Verona Massimiliano Bonifacio

only considering Acute Lymphoblastic Leukemia… • Original reports of clinical trials 10 • Case reports, biological studies, others 11 • Reviews and commentaries 98

A clinical case • D. (d.o.b. May 1984) was diagnosed with Philadelphia-neg, standard risk, TEL-AML1+, B-precursor common ALL in April 2009. • She was treated with a pediatric-like regimen (GIMEMA/AIEOP LAL1308 protocol) obtaining MRD-negative CR after induction. • She remained in complete MRD response until maintenance therapy completion and she went off-therapy in April 2011. • In November 2013, during a routine bone marrow check, a MRD relapse was documented (both by flow cytometry and molecular analysis) with rapidly raising values (from 1x10 -4 to 5x10 -2 ) • She was enrolled in the BLAST trial, obtaining complete MRD response after the 1 st cycle. It was decided to not proceed to allogeneic HSCT. She received 3 consolidation cycles of blinatumomab and ended treatment on May 2014. Bonifacio M, Tanasi I, et al. manuscript in preparation

A clinical case • In December 2014 (during the regular 6-month follow-up visit after blinatumomab end) she reported the suspicion of an unplanned pregnancy, which was confirmed by lab tests. • On 14 th August 2015 she delivered a healthy male baby. • In December 2015 a second MRD relapse was documented (both by flow cytometry and molecular analysis, 2x10 -3 ) and confirmed 1 month apart with slightly rising levels (3x10 -3 ). • She was treated with another cycle of blinatumomab between February and March 2016, obtaining a MRD response (positive below LLOQ). • She underwent allogeneic HSCT from sibling donor on 19 Apr 2016 (Endoxan – TBI as conditioning regimen). Bonifacio M, Tanasi I, et al. manuscript in preparation

A clinical case blinatumomab blinatumomab 1 ¡ 1 0,1 ¡ 10 -1 pregnancy ALLOSCT MRD level 0,01 ¡ 10 -2 0,001 ¡ 10 -3 0,0001 ¡ 10 -4 0,00001 ¡ 10 -5

Blinatumomab in MRD + B-ALL Inclusion criteria Pilot experience (German multicenter MT103-202 trial – n=21) • Patients with B-precursor ALL in first hematological CR with molecular failure or molecular relapse • MRD >10 -4 Confirmatory study (International multicenter MT103-203 trial – n=116) • Patients with B-precursor ALL in hematological CR with molecular failure or molecular relapse, including patients in 2 nd or later remission • MRD, defined as a level of ≥ 10 -3 in an assay with a minimum sensitivity of 10 -4

BLAST multicenter MRD study Causes of screening failure

BLAST multicenter MRD study Complete MRD response after cycle 1 Gokbuget N et al. ASH 2014

Multicenter MT103-211 study in rel/ref B-ALL Subgroup analyses of CR/CRh CR/CRh N % 95% CI All responders 189 43 36–50 Sex Female 70 46 34–58 Male 119 41 32–51 Age 18 to <35 90 43 33–54 35 to <55 46 46 31–61 55 to <65 28 36 19–56 ≥ 65 25 44 24–65 Prior Salvage 0 38 50 33–67 1 77 47 35–58 42 36 22–52 2 ≥ 3 32 34 19–53 16 38 15–65 Primary refractory Yes No 173 43 36–51 Prior HSCT Yes 64 45 33–58 No 125 42 33–51 Bone marrow blasts <50% 59 73 60–84 ≥ 50% 130 29 22–38 0 20 40 60 80 100 CR/CRh Rate, % Topp et al. Lancet Oncol 2015;16:57-66.

BLAST multicenter MRD study Long-term outcome Median (95% CI), Months Relapse-free 
 Overall 
 Survival* Survival Overall (n=112) 18.9 (12.3 - 35.2) 36.5 (19.2 - NR) By MRD complete response MRD complete responders (n=88) NR (6.0 - NR) 38.9 (33.7 - NR) MRD non-responders (n=24) 3.6 (1.6 - 5.7) 10.5 (3.8 - NR) By remission status First CR (n=75) 24.6 (18.7 - NR) 36.5 (20.6 - NR) Second/third CR (n=35) 11.0 (6.8 - 15.4) 19.1 (11.9 - NR) CR = complete remission; MRD = minimal residual disease; NR = not reached MRD response was defined as MRD < 10 -4 (minimum sensitivity 10 -4 ) *RFS censoring at HSCT or post-blinatumomab chemotherapy. Gokbuget N et al. ASH 2015

BLAST multicenter MRD study Relapse free survival 1.0 0.9 0.8 Survival Probability 0.7 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | RFS in MRD complete responders: 58% at 18 months 0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.5 | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.4 0.3 | | | | | | 0.2 0.1 0.0 Number of Subjects at Risk: 1: 85 77 68 63 60 57 34 33 24 23 15 15 8 7 3 3 3 3 1 0 2: 15 11 7 7 5 4 3 3 3 3 1 1 0 0 0 0 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 Study Month 1: MRD responder at cycle 1 (N = 85) Median 95% CI 23.6 ( 17.4, - ) 2: MRD non-responder at cycle 1 (N = 15) Median 95% CI 5.7 ( 1.6, 13.6) Complete MRD response (primary endpoint): MRD negative, no amplification in PCR (minimum sensitivity 10 -4 ) NR = not reached. The landmark analysis by MRD response included patients with overall survival of ≥ 45 days Gokbuget N et al. ASH 2015

Our experience in MRD + B-ALL Patient characteristics Patient Age Cytogenetics Previous treatments MRD Level of MRD at Molecular study entry 1.8x10 -2 #001 35y t(14;19?)(q32;q?) GIMEMA relapse female induction / 2 consolid / mainten 3.8x10 -2 #002 51y normal GIMEMA induction ( res ) failure male FLAI salvage ( CR MRD+ ) 2.2x10 -3 #003 46y normal NILG failure male induction / 1 consolid ( CR MRD+ ) #004 22y normal AIEOP induction ( late CR ) / failure 3x10 -3 male 1 consolid ( CR MRD+ ) #005 52y normal GIMEMA failure 1.3x10 -2 male induction / 2 consolid ( CR MRD+ ) #006 19y TEL/AML1+ AIEOP induction / consolid late relapse 5x10 -2 female (standard risk) / maintenance (>3 yrs) 6x10 -2 #007 32y normal NILG induction / reinduction ( late failure male CR )

Our experience in MRD + B-ALL Outcome Patient N° of Complete MRD Status at Outcome cycles Response after C1 transplant #001 Hematologic Death in remission female relapse à chemotx 2 Yes (at d+77 after HSCT due to acute GVHD) à CR #002 Death in remission Complete MRD male (at d+102 after HSCT due to wasting 3 Yes response encephalopathy of unknown origin) #003 Complete MRD Relapse and death male response 2 n.v. (after a second HSCT) ( flow cytometry ) #004 MRD response Relapse – alive in CR (chemotx + blina + DLI) male (positive below 2 Yes (+27 months after transplant) LLOQ) #005 Death in remission Complete MRD male 3 Yes (at +18 months after HSCT due to rapidly fatal response multifocal cerebral astrocytoma) #006 Alive female 4 Yes MRD relapse (severe pneumonia after HSCT) #007 Complete MRD Alive in CR male 3 Yes response (+7 months after transplant)

BLAST multicenter MRD study Role of SCT in pts with complete MRD response Transplant realization rate: 72% Cox model analyses of HSCT as time-dependent covariate for RFS First remission Second or later remission Hazard ratio: 2.26 (95% CI: 0.73, 6.97) 0.33 (95% CI: 0.11, 0.98) P 0.15 0.046 Simon-Makuch Plot of RFS (Landmark 45 days) First remission Second or later remission (N = 60) (N = 25) 1.0 1.0 Allo SCT Allo SCT No Allo SCT No Allo SCT Allo SCT prior to 0.8 0.8 Probability of RFS Probability of RFS relapse or censoring: Yes: 15 (60%) 0.6 0.6 No: 10 (20%) 0.4 0.4 Allo SCT prior to relapse or censoring: 0.2 0.2 Yes: 46 (77%) No: 14 (23%) 0.0 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study Month (Landmark Analysis Beginning at Study Day 45) Gokbuget N et al. ASH 2015

Blinatumomab and transplant: an open question First Blinatumomab Phase 2 Study in MRD-Positive ALL MRD complete response rate: 80% All responses within the first cycle of treatment Transplanted patients Non transplanted All patients (n=20) (n=9) patients (n=11) 61% Topp et al. J Clin Oncol 2011;29:2493-2498. Topp et al. Blood 2012;120:5185-5187.

Blinatumomab and transplant: an open question in relapsed/refractory patients Relapse-free survival Overall survival Median, months Median, months (95% CI) (95% CI) No censoring 5.9 (4.8–8.3) No censoring 6.1 (4.2–7.5) Censoring for HSCT 5.9 (4.2–6.9) Censoring for HSCT 5.1 (4.1–7.1) 1.0 1.0 0.8 0.8 Probability of RFS Probability of OS 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 4 6 10 14 16 0 4 6 10 14 16 2 8 12 18 2 8 12 18 Months Months Topp et al. Lancet Oncol 2015;16:57-66.

Blinatumomab and transplant: an open question in relapsed/refractory patients Relapse-free survival Overall survival Kantarjian et al. Cancer 2016 [epub]

Safety profile of blinatumomab Most common clinical AE are early, transient, reversible and do not require discontinuation of treatment • Pyrexia (60-90%) Ÿ Tremor (29-36%) • Headache (38-47%) Ÿ Fatigue (24-50%) Laboratory abnormalities (lymphopenia, leukopenia, C-reactive protein increase, decrease of immunoglobulins) are common. Fatal cases of infections occurred during or after treatment with blinatumomab, mainly in rel/ref patients and before that response could be assessed or in non-responder patients. Dose-dependent CNS adverse events occurred in all clinical studies: • Seizure, encephalopathy, ataxia, apraxia, aphasia, tremor • Reversible, no sequelae, no pathological changes in MRI • Main cause of treatment interruption in 31% of MRD+ and 15% of rel/ref pts • Predictive marker identified: low B:T cell ratio in peripheral blood (B:T<1:8)